Fibrosis is characterized by excessive deposition of scar tissue. Fibrosis is one of the largest groups of diseases for which there is no therapy. Fibrosis is responsible for morbidity and mortality associated with organ failure in a variety of chronic diseases affecting the lungs, heart, kidneys, liver and skin. It has been estimated that nearly 45% of all deaths in the developed world are caused by fibrotic conditions which include: cardiovascular disease, pulmonary fibrosis, diabetic nephropathy and liver cirrhosis (Wynn, 2004).
Fibrosis, and especially idiopathic pulmonary fibrosis, is a disease that is receiving increasing attention. Unfortunately, little is known about the pathogenesis of fibrosis and only recently the various cellular and molecular processes that contribute to this disease have been unveiled. The overall consensus is that fibrosis is a result of an imbalance in the immune and repair response following infection and/or tissue damage (reviewed by Lekkerkerker et al, 2012) These responses are the result of an intricate interplay between various cell types such as epithelial cells, fibroblasts, macrophages, fibrocytes, smooth muscle cells and endothelial cells. An imbalance in the activity in one or more of these cell types is expected to contribute to fibrosis.
A common theme of fibrotic diseases is the abnormal persistence of a particular specialized form of fibroblast, termed the myofibroblast (Gabbiani, 2003; Wynn, 2008). In the presence of profibrotic stimuli such as TGFβ and extra-cellular matrix (ECM) components (e.g. collagen I and fibronectin) fibroblasts differentiate into a myofibroblast phenotype, characterized by expression of α-smooth muscle actin (αSMA), secretion of collagen type I and III and increased migration and contractility (Wynn, 2007). These cells contribute to excessive wound healing and to excessive deposition of extracellular matrix proteins (fibronectin, collagen, and/or laminin). Several sources of fibroblasts have been put forward including proliferation of resident fibroblasts, generation of fibroblasts from epithelial cells through epithelial mesenchymal transition (EMT), differentiation of circulating fibrocytes or mesenchymal progenitor cells.
It is commonly believed that fibroblasts are the major contributor to the pool of myofibroblasts in fibrogenic foci (Lekkerkerker et al, 2012). A prerequisite for this contribution is the migration of fibroblasts towards foci and subsequent expansion and differentiation. Many factors have been identified over the years that activate the fibroblast and thereby enhance their migratory and/or proliferative capacity. These include growth factors PDGF, CTGF and TGFβ, but also chemokines such as CCL11 (Puxeddu et al., 2006), CCL21 (Pierce et al., 2007), CCL24 and CCL26 (Kohan et al., 2010).
TGFβ is a pleiotropic cytokine that has many versatile effects on the fibrogenic process in the lung, including but not restricted to the already discussed potentiation of EMT. TGFβ isoforms have also been shown to regulate deposition of many components of the ECM components (Eickelberg et al., 1999) and affect the migratory and differentiation potential of fibroblasts towards myofibroblasts (Scotton et al., 2007).
Another factor, PDGF, serves as a growth factor for mesenchymal cells and was shown to be essential in myofibroblast development as PDGF-A knock-out mice were devoid of alveolar myofibroblast progenitors (Bostrom et al., 1996).
In the past decades much effort has been put into the development of in vitro and in vivo models to unravel the molecular mechanisms regulating fibrotic processes in the lung (Lekkerkerker et al, 2012; Todd et al, 2012). It is, however, important to use these cells under physiological conditions and in a disease-relevant context. Hence, the biological screening assays utilizing primary cells in functional assays relevant for fibrosis in combination with functional genomics can give invaluable insight in the possible molecular mechanisms contributing to fibrosis and identify novel genetic targets for treatment of fibrosis.
The process of fibroblast migration and differentiation into myofibroblasts is still poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies. Therefore, there is a clear need to understand molecular and cellular processes underlying fibrosis, and, in particular, the biology of fibroblasts, and to provide new methods of identifying targets and compounds useful for treatment of fibrosis and fibrosis-related conditions.